Alzheimer's disease is a disease characterized by progressive dementia occurring from presenium to old age, and the number of domestic patients suffering the disease is said to be one million or more at present. It is anticipated that the number will certainly increase in the future in association with the aging population. Clinical symptoms of Alzheimer's disease are memory disorder, higher brain dysfunction (aphasia, apraxia, agnosia, and constructional apraxia), and the like. The symptoms are often observed commonly in other dementing disorders, and it is very difficult to make a definitive diagnosis of Alzheimer's disease only by the clinical symptoms. There has been no basic remedy for Alzheimer's disease to date. However, since a vaccine therapy was successful in model mice in 1999, there have been increasing expectations for development of basic remedies (non-patent literature 1). In order to effectively use such basic remedies, it is necessary to diagnose Alzheimer's disease in an early stage.
On the other hand, histopathological characteristics to determine Alzheimer's disease include senile plaques and neurofibrillary tangles. Main components of the former are amyloid β proteins which have β-sheet structures, and main components of the latter are hyperphosphorylated tau proteins. At present, an amyloid hypothesis is dominant in which a serious pathological change initially occurring at the onset of Alzheimer's disease is accumulation of amyloid β peptides (non-patent literature 2). It is known that in Alzheimer's disease, well before the onset of clinical symptoms, the above pathologic tissue change such as accumulation of amyloid β proteins has started in the brain. Therefore, detection of intracerebral amyloid β proteins as a marker will serve as one method for early diagnosis of the diseases in which amyloids accumulate, especially, Alzheimer's disease.
In such a view point, in recent years, radioactive contrast media have been studied that selectively bind to intracerebral amyloid β proteins for use in positron emission tomography (PET) and single-photon emission computed tomography (SPECT) (non-patent literature 3). As classical compounds having a high affinity to amyloids include congo red, thioflavin S, and thioflavin T, which are used in pathologic definitive diagnosis of Alzheimer's disease. It is difficult for many of them to pass through the blood-brain barrier, and even if they are intravenously administered, they hardly move into the brain. Moreover, recently, various structures have been found to have amyloid affinities, and one of those is curcumin (non-patent literature 4). Therefore, contrast media have been studied in consideration of the transmissiveness through the blood-brain barrier, and contrast media such as ISB, PIB, BF-168, (patent literature 1) and the like have been developed. Some of them have good results in clinical trials. However, since such contrast media use radionuclides such as 11C, 13N, 15O, 18F, and the like, there is a concern about adverse reaction due to radiation injuries, and in addition, a cyclotron facility needs to be provided nearby. Therefore, a diagnostic method that does not use radionuclides is desired.
As an example of a diagnostic method that does not use radionuclides is nuclear magnetic resonance imaging method (MRI). Recently, there have been reports that imaging of senile plaques by use of 19F-MRI was successful (patent literature 2, patent literature 3, and non-patent literature 5), and realization of such MRI diagnosis is highly expected. However, it is known that MRI is low in detectivity compared with PET and the like. Therefore, it is highly desired that high sensitivity MRI contrast media are developed for establishing a safe diagnosis method for Alzheimer's disease.
Further, with respect to in-vitro diagnostic agents, ELISA using specific antibodies for amyloid β peptides is being studied (non-patent literature 6). Recently, a hypothesis has become more dominant that a causative substance for neuronal cell deaths in Alzheimer's disease is rather not amyloid β peptides themselves but aggregates of amyloid β peptides such as amyloid β peptide oligomers (non-patent literature 7). Conventional ELISA which uses specific antibodies for amyloid β peptides can determine the quantity of amyloid β peptides in cerebrospinal fluid and serum, but cannot specifically detect aggregates of amyloid β peptides such as amyloid β peptide oligomers, the aggregates being considered as causing neurotoxicity.
Therefore, based on the hypothesis that the aggregates of amyloid β peptides such as amyloid β peptide oligomers are the cause for neuronal cell deaths occurring in Alzheimer's disease, methods and materials for specifically detecting aggregates of amyloid β peptides such as amyloid β peptide oligomers are being developed. Production of an antibody that specifically reacts with amyloid β peptide oligomers has been reported to date (non-patent literature 8). In a case where an antibody is used as an in-vitro diagnostic agent, it is necessary to perform cumbersome operations such as ELISA, which require several hours or more for conducting measurements. Moreover, an antibody is a high molecular weight protein, hardly passes through the blood-brain barrier, and thus cannot be used as a diagnostic imaging agent.
With respect to a contrast medium for MR imaging, a material having a nature of binding to amyloid β peptides is labeled with fluorine (19F), and is caused to bind to senile plaques appearing in the brain of an Alzheimer's disease patient. Then, a signal of 19F is detected, thereby imaging the senile plaques (non-patent literature 5, mentioned above). Generally, in any compound, a 19F signal is strong when the material is in a free state, and the 19F signal becomes weak when the material binds to a senile plaque. Therefore, a material is more desired that has a nature that the material locally repeats binding to and getting released from a senile plaque at a part where senile plaques are present, than a material that merely binds to a senile plaque.
With respect to a contrast medium for PET, a material having a nature of binding to amyloid β peptides is radioactively labeled and is caused to bind to a senile plaque appearing in the brain of an Alzheimer's disease patient, thereby imaging the senile plaque (non-patent literature 3, mentioned above). A radioactively-labeled material would cause fewer adverse reactions such as radiation injuries if it is removed in a short period of time. Therefore, it is desired that, after the material binds to a senile plaque and imaging is finished, the material is released from the senile plaque to be promptly excreted.
A keto-enol tautomerism is a nature of a compound indicating a difference between structures that the compound takes. Such a compound is present in an equilibrium mixture of a keto form and an enol form thereof. Therefore, depending on the environment, the compound exists, with a rate of the keto form higher than that of the enol form, or a rate of the enol form higher than that of the keto form. Moreover, the keto form and the enol form have various differences with each other, such as different colors, different absorption spectra, different fluorescence emissions, and different interactions with other substances, due to their structures. However, no reagent or diagnostic agent that focuses on and actively uses this phenomenon, the keto-enol tautomerism, has been developed.
It is known that curcumin having a 1,3-dicarbonyl structure binds to amyloid β peptides as described above (non-patent literature 4, mentioned above), and application thereof to a diagnostic imaging agent for Alzheimer's disease is being examined, which does not, however, positively utilizes the keto-enol tautomerism.